Temporary inhibition of AMPA receptors induces a prolonged improvement of motor performance in a mouse model of juvenile Batten disease.

Mutations in the CLN3 gene cause juvenile Batten disease, a fatal pediatric neurodegenerative disorder. The Cln3-knockout (Cln3(Δex1-6)) mouse model of the disease displays many pathological characteristics of the human disorder including a deficit in motor coordination. We have previously found that attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity in one-month-old Cln3(Δex1-6) mice resulted in an immediate improvement of their motor skills. Here we show that at a later stage of the disease, in 6-7-month-old Cln3(Δex1-6) mice, acute inhibition of AMPA receptors by a single intraperitoneal injection (1mg/kg) of the non-competitive AMPA antagonist, EGIS-8332, does not have an immediate effect. Instead, it induces a delayed but prolonged improvement of motor skills. Four days after the injection of the AMPA antagonist, Cln3(Δex1-6) mice reached the same motor skill level as their wild type (WT) counterparts, an improvement that persisted for an additional four days. EGIS-8332 was rapidly eliminated from the brain as measured by HPLC-MS/MS. Histological analysis performed 8 days after the drug administration revealed that EGIS-8332 did not have any impact upon glial activation or the survival of vulnerable neuron populations in 7-month-old Cln3(Δex1-6) mice. We propose that temporary inhibition of AMPA receptors can induce a prolonged correction of the pre-existing abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease.